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Journal of Chemotherapy Vol. 10 - n. 6 (469-473) - 1998

<$i zithromycin Compared with Minocycline

A
in the Treatment of Acne Comedonica
and Papulo-Pustulosa
F. GRUBER 1 - H. GRUBISIC-GREBLO 2 - M. KASTELAN 1 - I. BRAJAC 1
M. LENKOVIC 1 - G. ZAMOLO 3>

1 Department of Dermatology, Clinical Hospital Center, 2 Department of Social Medicine, Medical School, and
3 Department of Pathology, Medical School, Rijeka, Croatia.

Correspondence: Prof. Francesco Gruber MD, PhD, Department of Dermatology, Clinical Hospital Center,
Kresimirova 42, 51000 Rijeka, Croatia. Tel. +385.51.658281; fax +385.51.337536.

Summary
This open study was conducted in 72 outpatients with acne vulgaris, to
compare the clinical efficacy and tolerability of azithromycin and minocycline.
Azithromycin was administered as a single oral dose (500 mg/day) for 4 days
in four cycles every 10 days and minocycline was administered 100 mg daily
for 6 weeks. Improvement was assessed 6 weeks after initiation of treatment
with a four-graded scale. A satisfactory clinical response was observed in
75.8% of the patients treated with azithromycin and in 70.5% of those treated
with minocycline. There were no significant differences between these two acne
treatments in terms of reduction of the number of lesions (p> 0.05). Both
agents were well tolerated and mild side effects were reported in 10.3% of
azithromycin and 11.7% of minocycline treated patients. We conclude that
azithromycin is at least as clinically effective and well tolerated as minocycline
as treatment of facial comedonic and papulopustular acne.

Key words: Acne vulgaris, azithromycin, minocycline, therapy, tolerability.

INTRODUCTION sebaceous glands in response to androgen hor-

Acne vulgaris is one of the most common
diseases of the pilo-sebaceous unit of the skin.
The most common localizations of the disease
are the face, the upper part of the chest and
back. Generally the disorder occurs at the onset
of puberty, due to the increased function of the
mones. Another important aspect of the
etiopathogenesis is abnormal keratinization of
the follicular duct, blocking the aperture, and
the presence of the anaerobic Gram-positive
Propionibacterium acnes 1,2. These bacilli have
lipases that split the sebum triglycerides into
free fatty acids. P. acnes also generate various

© E.I.F.T. srl - Firenze ISSN 1120-009X

470 F. GRUBER - H.
proinflammatory mediators, chemotactic factors
and can activate the complement. The initial
cell infiltrate in acne consists of CD4 lympho-
cytes, however later neutrophils predominate.
They have an important role in the inflammato-
ry process of the disease 3,4.
The intensity and duration of the lesions
vary and the disease can comprise comedones,
papulopustules, cysts and nodules, and can
result in scarring, psychological frustration and
even cause difficulties at work 5.
Antibiotics are useful in many cases of acne,
but because they have to be administered sever-
al times a day, there can be some problems
with compliance. The introduction of new ther-
apeutic schedules with long half-life antibiotics
permits less frequent dosage.
The purpose of this study was to assess and
compare the therapeutic efficacy and tolerabili-
ty of azithromycin, a new long acting azalide,
with minocycline in the treatment of patients
with papulopustular acne.
PATIENTS AND METHODS
Seventy-two patients with moderate to
severe acne vulgaris entered this open, non-
randomized and comparative study. All patients
had a complete physical examination before
enrollment. The extent of the disease was
assessed clinically before treatment started and
at 2-week intervals. The mean duration of the
disease prior to enrollment was 4.8 years (1-8
years). The diagnosis was performed by a der-
matologist and graded using the classification of
Plewig and Kligman 6.
Inclusion criteria
Eligibility criteria for the study were young
males and females with acne comedonica and
papulo-pustulosa, present on the face, shoul-
ders, back and chest, unresponsive to topical
therapy, who were older than 16 years.
Exclusion criteria
Exclusion criteria were: female patients on
oral contraceptives or who had stopped soon
before enrollment, pregnant females, patients
with disorders of the gastrointestinal system,
patients with associated endocrinological dis-
GRUBISIC-GREBLO - M. KASTELAN - I. BRAJAC - M. LENKOVIC - G. ZAMOLO
eases, patients with known hypersensitivity to
macrolides or tetracyclines and other types of
acne (professionalis, drug induced, detergens,
cosmetica).
Treatment
The acne patients were assigned, according
to a predetermined open study protocol, to one
of the following two groups. All subjects were
instructed to take the drug once-daily before
breakfast. Patients assigned to group I received
orally azithromycin 500 mg (Sumamed, Pliva),
for 4 days every 10 days, for a total of four
cycles. Patients in group II received minocycline
100 mg (Minocin) daily for 6 weeks. When
needed, supportive measures included topical
2% salicylic acid solution to control seborrhea.
The nature and purpose of the trial were
explained to the patients and a verbal informed
consent was obtained from them.
Efficacy and safety assessment
Clinical assessment was performed by the
same dermatologist at the beginning of the trial
and then every 2 weeks after the start of treat-
ment. The lesion count was made for the face
because it is known that lesions on the back
clear more slowly. The response at the end of
the trial was classified by the dermatologist as
either good improvement (75% or greater
reduction in the acne lesion count), moderate
improvement (50-75% reduction in the lesion
count), slight improvement (20-50% reduction
in the lesions) or in comparison with the pre-
treatment assessment. The patients were also
asked to report any side effects at every follow-
up visit, and hematological and liver function
tests were performed before and after treat-
ment.
Statistical analysis
The statistical analysis was undertaken using
the chi square test and t-test.
RESULTS
Out of a total of 72 study patients with acne
vulgaris 32 were treated with azithromycin and
40 with minocycline. The demographic charac-
AZITHROMYCIN COMPARED WITH MINOCYCLINE IN THE TREATMENT OF ACNE COMEDONICA AND PAPULO-PUSTULOSA 471

teristics and baseline clinical aspects show that Three patients from the group treated with
the two groups were similar for sex ratio, age, azithromycin and 4 from the minocycline group
weight and disease severity (Table 1). Of the failed to return for follow-up visits; in this sec-
enrolled patients 63 were evaluable: 29 treated ond group one patient was excluded for not
with azithromycin and 34 with minocycline. adhering to the treatment and one because of
side effects.
The results of the treatment in the evaluable
TABLE 1 - Characteristics of the two treatment groups.
patients are summarized in Table 2. Both
Azithromycin (N=32) Minocycline (N=40) groups started with a similar number of papulo-
Sex Male 16 18 pustular lesions (25±5.8 vs 24.4±5.3; p>
Females 16 22 0.05).
At baseline 72.4% of the patients treated
Age (range) 21.3 (18-24) 22.6 (16-25)
with azithromycin were in grade III of papulo-
Duration of acne 4.6 yr 4.9 yr pustular acne (according to Plewig and

TABLE 2 - Results of treatment of acne vulgaris.

Azithromycin (N=29) Minocycline (N=34)
Patients Number of lesions Patients Number of lesions
at baseline after 6 weeks at baseline after 6 weeks
1. 26 5 1. 28 9
2. 24 4 2. 26 5
3. 29 5 3. 21 4
4. 30 3 4. 20 3
5. 26 21 5. 29 10
6. 20 8 6. 24 7
7. 21 10 7. 29 11
8. 25 20 8. 28 9
9. 23 8 9. 28 10
10. 22 6 10. 23 7
11. 29 24 11. 22 7
12. 26 8 12. 28 8
13. 20 10 13. 26 7
14. 21 25 14. 24 7
15. 30 9 15. 28 23
16. 22 8 16. 22 12
17. 26 15 17. 20 17
18. 24 16 18. 23 12
19. 27 14 19. 21 11
20. 20 12 20. 27 22
21. 34 15 21. 22 18
22. 21 11 22. 28 23
23. 39 31 23. 24 20
24. 35 28 24. 29 24
25. 35 29 25. 31 26
26. 19 10 26. 34 29
27. 15 – 27. 31 20
28. 19 3 28. 36 29
29. 17 1 29. 18 10
30. 18 3
31. 17 2
32. 12 –
33. 15 1
34. 19 3
725 359 831 409
x1= 25±5.8 x2= 12.3±8.7 x1= 24.4±5.3 x2= 12.0±8.4
t=0.1612
p>0.05
472 F. GRUBER
Kligman), i.e. with 20-30 lesions on one side;
13.7% in grade IV and 13.7% in grade II. At
the end of the trial only 20.6% remained in
grade III, while the majority were in grade I and
II (44.0% and 31.0% respectively).
At baseline 70.5% of patients treated with
minocycline were in grade III, 13.0% in grade
II, and the same percentage in grade IV of
papulopustular acne. At the end of the trial the
majority of these patients (47%) were in grade
I, while 29.0% were in grade II and 23.5% in
grade III.
Among the patients treated with
azithromycin, 75.8% showed good, moderate
or slight improvement, while 70.5% of the
patients treated with minocycline showed such
improvement. So, at the end of the study there
were no significant differences between the two
treatment groups in terms of reduction of the
number of lesions before and after the end of
the trial.
Side effects are summarized in Table 3. No
significant changes were noted in blood count;
only 3 patients on azithromycin had slight gas-
trointestinal troubles (one of them also had
slight deterioration of the liver function tests
which returned to normal in a month after
treatment was stopped). Four patients in the
minocycline group experienced side-effects
(gastrointestinal or vertigo).
TABLE 3 - Side effects experienced by the treated
patients.
Side effects Azithromycin (N=29) Minocycline (N=34)
Vertigo – 2
Nausea 1* 1 The small number of patients in the study
Abdominal pain 1 –
Diarrhea 1 1
Total 3 (10.3%) 4 (11.7%)
* The patient had slightly increased liver tests
DISCUSSION
Antibiotics are frequently used topically or
systemically in the treatment of acne, but
Propionibacterium acnes is becoming resistant
to a variety of antibiotics. Azithromycin has
been shown to be highly effective in the treat-
ment of a number of various inflammatory skin
- H. GRUBISIC-GREBLO - M. KASTELAN - I. BRAJAC - M. LENKOVIC - G. ZAMOLO
diseases, and for this reason we undertook this
trial in patients with acne. In this open compar-
ative trial azithromycin yielded satisfactory ther-
apeutic effects in comparison with minocycline
in acne vulgaris patients with non-inflammatory
and inflammatory lesions.
Good or moderate clinical improvement was
obtained in 70.5% of the patients treated with
minocycline, while in the group treated with
azithromycin excellent results were obtained in
75.8% of the patients (p>0.05).
There is agreement that orally given tetracy-
clines, especially minocycline are effective drugs
in the treatment of acne 7-9.
Azithromycin has a wide spectrum of
action, low toxicity and high tissue concentra-
tion, even though its serum concentration is
low. It also has a long half-life. The minimum
inhibitory concentration (MIC90) of azithromycin
against clinical isolates of Propionibacterium
acnes is 0.15 mg/L similar to that of other
macrolides 10. There are only a few studies on
the treatment of acne with azithromycin; our
results are in concordance with similar results
reported by Pavone 11,12, who also used 500
mg daily of azithromycin.
In recent years there is increasing evidence
that minocycline can, on occasion, produce
unpleasant or severe adverse effects. It can pro-
voke not only a disturbing hyperpigmentation
of the skin, mucous membranes and internal
organs, but can also induce immunologically
mediated reactions such as liver damage, ery-
throderma and eosinophilic pneumonitis 13-15.
Because of these side effects, alternative drugs
are required during long term treatment with
minocycline.
precludes firm statistical verification, neverthe-
less, on the basis of the results of our trial it
may be concluded that azithromycin is a suffi-
ciently safe and effective drug in the therapy of
moderate to severe acne, in cases that fail to
respond to topical treatment. In our experience
the simple regime, i.e. once-daily treatment, led
to good compliance. The high cost of the drug
may be one disadvantage of its use.
REFERENCES
1 Melnik B, Plewig G. Neue lipidbiochemische Aspekte in
der Pathogenese der follikularen Verhornungsstorung bei Acne
AZITHROMYCIN COMPARED WITH MINOCYCLINE IN THE TREATMENT OF ACNE COMEDONICA AND PAPULO-PUSTULOSA
vulgaris. Z Hautkr 1988; 63: 591-596.
2 Vowels BR, Yang S, Leyden JJ. Induction of proinflam-
matory cytokines by a soluble factor of Propionibacterium
acnes: implications for chronic inflammatory acne. Infect
Immun 1955; 63: 3158-3165.
3 Webster GF. Inflammation in acne vulgaris. J Am Acad
Dermatol 1995; 33: 247-253.
4 Holland KT, Aldana O, Bojar RA et al.
Propionibacterium acnes and acne. Dermatology 1998; 196:
67-68.
5 Lim CC, Tan TC. Personality, disability and acne in col-
lege students. Clin Exp Dermatol 1991; 16: 371-373.
6 Plewig G, Kligman AM. Acne. Morphogenesis and treat-
ment. Berlin, Heidelberg, New-York: Springer 1975: 38-65.
7 Eady EA, Jones CE, Gardner KJ, et al. Tetracycline-
resistant propionibacteria from acne patients are cross-resis-
tant to doxycycline, but sensitive to minocycline. Br J
Dermatol 1993; 128: 556-560.
8 Rossman RE. Minocycline treatment of tetracycline-resis-
tant and tetracycline-responsive acne vulgaris. Cutis 1981; 27:
473
196-197.
9 Leyden JJ. Absorption of minocycline hydrochloride and
tetracycline hydrochloride: effect of food, milk, and iron. J Am
Acad Dermatol 1985; 12: 308-312.
10 Peters DH, Friedel HA, McTavish D. Azithromycin. A
review of its antimicrobial activity, pharmacokinetic properties
and clinical efficacy. Drugs 1992; 44: 750-799.
11 Pavone P. Azitromicina versus minociclina nel tratta-
mento dell’ acne volgare. Chron Derm 1994; 4: 867-872.
12 Fernandez-Obregon AC. Azithromycin for the treatment
of acne (letter). Intern J Dermatol 1997; 36: 239-240.
13 Pepine M, Flowers FP, et al. Extensive cutaneous
hyperpigmentation caused by minocycline. J Am Acad
Dermatol 1993; 28: 295-297.
14 Gough A, Chapman S, Wagstaff K, Emery P, Elias E.
Minocycline-induced autoimmune hepatitis and systemic lupus
erythematosus-like syndrome. Br Med J 1996; 312: 169-172.
15 Dykhuisen RS, Zaidi AM, Godden DJ, Jegarah S,
Legge JS. Minocycline induced pulmonary eosinophilia. Br
Med J 1995; 310: 1520-1521.